tbuckley/cabot-search huggingface dataset:
Abstract 71: Integrated-omics analysis identifies the druggable achilles targets to sensitize cancer cells with gefitinib resistance
Authors: Eun-Ji Kwon, Haeseung Lee, Hyuk-Jin Cha
Journal: Cancer Research (2022)

Abstract Limited eligibility remains one of major drawbacks of target therapeutics as the oncogenic dependency is only determined by mutation status of a target. In order to extend the eligibility of target therapeutics, transcriptome profiles of patients have been examined to better delineate sensitivity of target therapeutics. In this study, we took advantage of multiple large datasets such as cancer cell line transcriptome data (CCLE), drug response data (CTRP), and gene dependency data (Achilles Project) to determine the sensitivity markers of tyrosine kinase inhibitors currently approved by FDA. In particular, EGFR inhibitors (iEGFR: lapatinib, gefitinib and erlotinib) revealed clear sensitivity cluster of cell line regardless of EGFR mutation status. Comparative analysis between sensitive (iEGFR-S) and resistant (iEGFR-R) cell groups revealed that integrated gene signatures such as chemokine, GPCR, and PI3K-Akt signaling pathway, were predicted as putative determinants of iEGFR susceptibility. Through integrated analysis of gene dependency data, among several Achilles’ targets (of which depletion increases vulnerability), predicted in iEGFR-R cells group, druggable Achilles’ targets (available to accompanied drugs) such as CCR6, AURKA and mTOR were identified as putative targets for sensitizing iEGFR-R group to iEGFR. Following biochemical studies validated the clear sensitizing effect of the pharmacological inhibitor for each predicted target, in the isogenic cell models with acquired iEGFR resistance. In addition, prediction and following biochemical validation, we demonstrated that the CCR6 inhibition significantly attenuated resistance of iEGFR by repressing mitochondrial ROS (mt-ROS), of which induction by iEGFR rescued cell death. These data suggest that integrated-omics analysis would be a useful approach to extend eligibility and improve the efficacy of target therapeutics. Citation Format: Eun-Ji Kwon, Haeseung Lee, Hyuk-Jin Cha. Integrated-omics analysis identifies the druggable achilles targets to sensitize cancer cells with gefitinib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 71.
Abstract 5895: Examining the association between arsenic exposure and cancer risk among Canadian adults
Authors: Katherine Pullella, Vicky C. Chang, Shelley A. Harris, Anthony J. Hanley, John R. McLaughlin, Jan Lubinski, Steven A. Narod, Joanne Kotsopoulos
Journal: Cancer Research (2022)

Abstract Background: Arsenic is a highly prevalent environmental toxin and an established carcinogen for cancers of the skin, bladder, and lung. Emerging evidence also suggests that arsenic exposure may be a risk factor for breast and other cancers. Previous studies have been conducted in populations with endemically high levels of arsenic; however, the impact of chronic exposure to low levels is not known. Thus, the purpose of this study was to describe the arsenic exposure in Canadian adults and to evaluate the association between arsenic status and cancer risk. Methods: The Canadian Health Measures Survey (CHMS) is an ongoing, nationally representative survey that collects self-reported and objective health measures, including biomonitoring data, from participants in biennial cycles. This analysis utilized total, inorganic and organic urinary arsenic biomarkers (µg/L) from Cycles 1-5 (2007-2017) of the CHMS. Incident cancers were ascertained through a linkage to the Canadian Cancer Registry. Arsenic exposure was described using weighted percentiles, and Cox proportional hazards regression models were used to estimate the association between arsenic exposure and cancer risk (overall and site-specific). Results: This analysis included 10,000 individuals, aged 18-80. The median total urinary arsenic level was 7.5 ug/g of creatinine. Preliminary models showed that levels of inorganic arsenic exposure above the geometric mean (&amp;gt; 4.5 µg/L) were associated with a 3-fold increased risk of developing any cancer (HR = 3.58; 95%CI 1.63-7.85), compared to those with lower levels. Site-specific risk modelling is ongoing and preliminary results will be presented. Significance: This study found inorganic arsenic exposure may be associated with an increased risk of developing cancer. To our knowledge, this study is the first to ascertain national estimates of arsenic exposure and provide insight on the relationship between arsenic exposure and cancer risk in Canadian adults. These findings are critical for developing population-level interventions to reduce the Canadian, and global, cancer burden. Citation Format: Katherine Pullella, Vicky C. Chang, Shelley A. Harris, Anthony J. Hanley, John R. McLaughlin, Jan Lubinski, Steven A. Narod, Joanne Kotsopoulos. Examining the association between arsenic exposure and cancer risk among Canadian adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5895.
Abstract 1573: Paradoxical roles of peritumoral myofibroblasts in intrahepatic cholangiocarcinoma growth and metastasis
Authors: Cheng Tian, Liyuan Li, Yizhen Li, Wentao Yang, Li Fan, Anthony Brown, Michelle Morrison, Jun J. Yang, Evan S. Glazer, Liqin Zhu
Journal: Cancer Research (2022)

Abstract Background and Rationale: Intrahepatic cholangiocarcinoma (iCCA) is an aggressive type of primary liver cancer characterized by its highly desmoplastic stroma. Compared to the ample knowledge on the protumorigenic functions of iCCA intratumoral myofibroblasts (iMFs), little is known about the activation status of MFs in the tumor-surrounding liver (peritumoral myofibroblasts, pMFs) and their potential role in iCCA development. Results: We examined MF activation in both patient iCCA tumors and an iCCA orthotopic allograft mouse model. We found there was a significant, tumor-induced activation and accumulation of pMFs at the tumor border. Using an in vitro spheroid coculture system, we confirmed that iCCA-liver interaction induced rapid pMF activation at their interface. We found that MFs mixed within tumor spheroids as iMFs had a pro-proliferative effect on iCCA tumor cells similar to the previous reports. However, when the same MFs were seeded around iCCA spheroids as pMFs, they exerted a strong suppressive effect on tumor cells growth. Interestingly, prolonged iCCA-pMF coculture elicited marked tumor cell invasion and dissemination which did not occur in iCCA-iMF coculture. We found vascular cell adhesion protein 1 (Vcam1), a glycoprotein that has been implicated in solid tumor metastasis, was part of the dynamic regulation of tumor cell behaviors by iCCA-pMF interaction. Vcam1 was upregulated in the tumor cells at the early, growth-suppressing phase of iCCA-pMF interaction both in vitro and in vivo, and was then downregulated in tumor cells when they started to disseminate. Systemic blocking of Vcam1 activity in iCCA allograft mouse models using a Vcam1 neutralizing antibody slowed the primary tumor growth but promoted tumor cell dissemination. Conclusion: Our data suggest that pMFs are beyond simple pro- or anti-tumorigenic in iCCA development. iCCA development induces rapid activation and accumulation of pMFs at the tumor border which suppress tumor growth at early stage but eventually elicit tumor cell dissemination at late stage. Citation Format: Cheng Tian, Liyuan Li, Yizhen Li, Wentao Yang, Li Fan, Anthony Brown, Michelle Morrison, Jun J. Yang, Evan S. Glazer, Liqin Zhu. Paradoxical roles of peritumoral myofibroblasts in intrahepatic cholangiocarcinoma growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1573.
Abstract LB098: Integrative approaches to modulate antigen presentation and boost cancer immune response
Authors: Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, X. Shirley Liu, Myles Brown
Journal: Cancer Research (2022)

Abstract Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but patients with impaired MHC-I and/or MHC-II expression show inferior response. We observed differential expression patterns for MHC-I and MHC-II in cancer cells and applied multiple approaches to examine their regulatory mechanisms. To identify the modulators of MHC-I, we combined FACS-based genome-wide CRISPR screens with data-mining from public data. We identified TRAF3, a suppressor of the NFkB pathway, as a negative regulator of MHC-I. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. In contrast to MHC-I, the expression of MHC-II shows dramatic intra- and inter-sample heterogeneity. To identify the regulators of MHC-II, we conducted data-mining of the transcriptomic and proteomic data from Cancer Cell Line Encyclopedia (CCLE) and multiple melanoma clinical cohorts. We found that a higher cancer-cell-intrinsic MHC-II level is significantly associated with better anti-PD-1 response, and that the Hippo signaling pathway can regulate MHC-II expression in melanoma cells. Our findings provide preclinical rationales for increasing cancer cell MHC-I/MHC-II expression to enhance sensitivity to immunotherapy. Citation Format: Shengqing Gu, Wubing Zhang, Xiaoqing Wang, Peng Jiang, Gordon J. Freeman, Scott J. Rodig, Henry Long, Benjamin E. Gewurz, F. Stephen Hodi, X. Shirley Liu, Myles Brown. Integrative approaches to modulate antigen presentation and boost cancer immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB098.
Abstract 4002: Identification of signal transduction pathway activity with potential clinical target in high-grade serous ovarian carcinoma
Authors: Phyllis Van der Ploeg, Yvonne J.W. Wesseling-Rozendaal, Eveline C. Biezen-Timmermans, Jurgen M.J. Piek
Journal: Cancer Research (2022)

Abstract Background: High-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer. It has a high mortality rate, even after successful first-line treatment with debulking surgery and chemotherapy. Although therapeutic options for targeted therapy are rapidly expanding, identification of patients who respond to these therapies remains a challenge. In recognition of the importance of the functional phenotype of cancer cells, Verhaegh et al. (Cancer Res 2014) developed assays to measure functional activity of signal transduction pathways (STPs) based on mRNA expression levels of pathway-specific target genes. In this study, we aimed to identify HGSCs with STP activity with a potential clinical target by comparing their activity with STP activity in normal Fallopian tube epithelium (FTE), the tissue of origin of most HGSCs. Methods: We included 50 primary tumor samples taken prior to start of chemotherapy of postmenopausal patients diagnosed with advanced stage HGSC and 9 morphologically normal FTE samples of healthy postmenopausal women. Using pathway assays, we assessed functional pathway activity of the androgen receptor (AR), estrogen receptor (ER), PI3K, MAPK, Hedgehog, TGFβ and Notch pathways. Differences in STP activity between groups were compared with Mann-Whitney U tests. Cut-off value for aberrant STP activity was defined as two standard deviations above the mean value of STP activity measured in FTE samples. Results: In the HGSC group we observed lower median ER (p &amp;lt; 0.001) pathway activity and higher median PI3K (p &amp;lt; 0.001), Hedgehog (p &amp;lt; 0.001) and TGFβ pathway (p = 0.020) activity as compared to the FTE group. In individual HGSC samples, aberrant activity was identified for the MAPK (n = 10), PI3K (n = 22), Hedgehog (n = 28) and TGFβ (n = 21) pathways. Frequently observed combinations of aberrant STP activity were Hedgehog/TGFβ (n = 12) and Hedgehog/PI3K (n = 9). In total, we identified at least one STP with potential clinical target in 88% (44/50) of HGSC samples. Conclusions: Our analysis enabled the identification of STP activity with a potential clinical target in 88% of the analyzed HGSC samples. Differentiation between normal and aberrant STP activity could have clinical utility in the selection of HGSC patients for targeted therapy. A prospective study (STAPOVER) has been designed to demonstrate clinical utility. Citation Format: Phyllis Van der Ploeg, Yvonne J.W. Wesseling-Rozendaal, Eveline C. Biezen-Timmermans, Jurgen M.J. Piek. Identification of signal transduction pathway activity with potential clinical target in high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4002.
Abstract 131: The role of p66ShcA in the melanoma oncogenesis process
Authors: Eduardo Cepeda Canedo, Sonia Del Rincon, Peter Siegel, Michael Witcher, Josie Ursini-Siegel
Journal: Cancer Research (2022)

Abstract Background: The identification of crucial driver mutations that affect the MAPK signaling pathway (BRAF, NRAS, NF1) in melanomas, has allowed for the development of targeted therapies and shed light on the process of melanocyte transformation. Gain of function mutations in proteins within the Ras/MAPK pathway in melanocytes leads to the formation of benign neoplasms, or nevi. Multiple mechanisms prevent the transformation of nevi into invasive cancer, namely, oncogene-induced senescence (OIS) and immunosurveillance. Of interest to the melanomagenesis process is the p66ShcA redox protein. We have found that compared to other solid cancers, the majority of primary human melanomas, patient-derived xenografts and melanoma cell lines strongly overexpress p66ShcA, an adaptor protein that induces production of reactive oxygen species (ROS) in response to stress stimuli. Indeed, UV light, increases p66ShcA levels and p66ShcA-induced oxidative stress, which is relevant to this disease as sun exposure contributes significantly to melanoma development. We hypothesized that p66ShcA may play a crucial role in the early steps of melanocyte transformation, possibly by contributing to the overriding of OIS and immune surveillance. Methods: Melanoma initiation and progression will be examined in a known transgenic mouse model (Tyr::CRE/brafCA/ptenlox/lox) either in the presence of endogenous levels of p66ShcA or in an inducible p66ShcA over-expression setting. The necessity of p66ShcA-high expression for melanocyte BRAFV600E-transformation will be tested in immortalized melanocytes. Lastly, to explore the potential selection advantage conferred by p66ShcA, its expression will be silenced in a panel of known melanoma cell lines. Clonogenic assays as well as mouse xenografts will be performed. Results: TCGA melanoma datasets, immunoblot analysis of human melanoma cell lines (n&amp;gt;10), and a collection of metastatic patient-derived xenografts (PDX) (n=6) indicate uniformly elevated p66ShcA levels compared to other cancer types. Knock-down of p66ShcA in multiple melanoma cell lines reduces their clonogenic potential. This reduction in colony formation is independent of driver mutation (e.g., BRAF, NRAS, NF1). Suggesting that p66ShcA may sustain melanoma proliferation. Furthermore, xenografts of the murine YUMM1.7 cell line (braf mutant, cdkn2a null and pten null) in immune-deficient and immune-competent mice indicate that loss of p66ShcA (YUMM1.7 p66ShcA-KO) delays tumor formation, specifically in mice with an intact immune system. Citation Format: Eduardo Cepeda Canedo, Sonia Del Rincon, Peter Siegel, Michael Witcher, Josie Ursini-Siegel. The role of p66ShcA in the melanoma oncogenesis process [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 131.
Abstract LB042: Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor
Authors: Ben Atwell
Journal: Cancer Research (2022)

Abstract Overexpression and/or overactivation of the Epidermal Growth Factor Receptor (EGFR) is oncogenic in several tumor types yet targeting the kinase domain of wildtype EGFR has had limited success. EGFR has numerous kinase-independent roles, one of which is accomplished through the Sorting Nexin-dependent retrotranslocation of EGFR to the nucleus, which is observed in some metastatic cancers and therapeutically resistant disease. Here, we have utilized the BAR domain of Sorting Nexin 1 to create a peptide-based therapeutic (cSNX1.3) that promotes cell death in EGFR-expressing cancer. We evaluated the efficacy of cSNX1.3 in tumor-bearing WAP-TGFα transgenic mice (an EGFR-dependent model of breast cancer), where cSNX1.3 treatment resulted in significant tumor regression without observable toxicity. Evaluation of remaining tumor tissues found evidence of increased PARP cleavage, suggesting apoptotic tumor cell death. To evaluate the mechanism of action for cSNX1.3, we found that cSNX1.3 binds the C-terminus of the EGFR kinase domain at an interface site opposite the ATP binding domain with a K d of ~4.0 µM. In vitro analysis found that cSNX1.3 inhibits both long-term EGF-dependent AKT and ERK activation, as well as nuclear localization of EGFR. To determine specificity, we evaluated cancer cell lines expressing wildtype EGFR (MDA-MB-468, BT20 and A549), mutant EGFR (H1975) and non-transformed lines (CHO and MCF10A). Only transformed lines expressing wildtype EGFR responded to cSNX1.3, while mutant EGFR and normal cells responded better to the EGFR kinase inhibitor (Sapitinib). Phenotypically, cSNX1.3 inhibits EGF-, NRG-, and HGF-dependent migration, but not HA-dependent migration. Together, these data indicate that targeting retrotranslocation of EGFR may be a potent therapeutic for RTK-active cancer. Citation Format: Ben Atwell. Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB042.
Abstract 5757: Germline and somatic mutational landscape of Chinese early-onset colorectal cancers
Authors: Xiancheng Zeng, Junhao Liu, Yurong Luo, Hailiang Li, Xinyi Liu, Mengli Huang
Journal: Cancer Research (2022)

Abstract Background: The incidence of colorectal cancer (CRC) in young people, described as early-onset colorectal cancer (EOCRC) has been rising up in decades. Apart from definite familial genetic disease, a considerable proportion of EOCRC remained unknown of the mechanism. Characterizing the difference in genomic features of EOCRC and late-onset CRC (LOCRC) would help us to understand it. Methods: A total of 1777 Chinese CRC patients diagnosed in 2019-2020 were included. 489 patients under 50 years were defined as EOCRC. A 733-gene panel next-generation sequencing (NGS) testing and measurement of tumor mutational burden (TMB) levels based on the panel were conducted in all patients’ tumor specimen. Lynch syndrome (LS) was defined as patients harboring at least one non-benign germline mutation in four LS MMR genes (MLH1, MSH2, MSH6, PMS2). Results: 43 of 489(8.8%) cases and 54 of 1288 (4.2%) cases were MSI-H in EOCRC and LOCRC, separately. Excluded 97 LS patients (84.3% in MSI-H EOCRC and 72.0% in MSI-H LOCRC), the proportion of non-LS MSI-H in EOCRC and in LOCRC were 1.8% and 1.7%, separately. Compared to non-LS MSI-H LOCRC, EOCRC has higher germline mutational frequencies in APC, CD74, ATM, BCL2L11, CHEK2, and RECQL4 genes and somatic mutational frequencies in APC, ERCC4, CHD2, ARHGAP5, CASP8, and ATM genes. In non-LS MSS patients, germline mutations in CHEK2, NBN and POLE genes, somatic SNV/indels in RNF43, ATR, AFF3, JAK2, POLG, CHD2 genes and somatic copy number gain in genes on chromosome 8 (ZNF703, FGFR1, MYC, PTK2) occurred more frequently in EOCRC. KEGG enrichment analysis in somatic mutations indicated significant overexpressed MAPK signaling pathway. The TMB level was significantly lower in non-LS MSS EOCRC than in LOCRC. Conclusions: The proportion of non-LS MSI-H in Chinese EOCRC and LOCRC were approximate. Non-LS MSS EOCRC had marked chromosome 8 somatic copy number gain and MAPK signaling pathway, indicating the potential mechanism. The comparative lower TMB level in EOCRC was concordance with previous studies and the correlations between low TMB level and high CNV burden also corroborate the etiopathogenesis. Citation Format: Xiancheng Zeng, Junhao Liu, Yurong Luo, Hailiang Li, Xinyi Liu, Mengli Huang. Germline and somatic mutational landscape of Chinese early-onset colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5757.
Abstract 3368: Biomarkers of precancerous colorectal cancer stages identified by transcriptome profiling
Authors: Anna Siskova, Veronika Vymetalkova, Pavel Vodicka, Giulio Ferrero, Alessio Naccarati, Chuanpit Hampel, Regine Schneider-Stock
Journal: Cancer Research (2022)

Abstract A colorectal adenoma, an aberrantly growing tissue that arises from the intestinal epithelium is considered a precursor of colorectal cancer, the third most common cancer worldwide. In the presented study, we performed a whole transcriptome analysis of 18 fresh frozen colorectal adenomas and their adjacent mucosa from the Czech and Italian populations. Samples were matched for histology and sex. The libraries were sequenced through NovaSeq6000 with a paired-end approach (2 × 150 bp) and with 100 million reads per sample. The enrichment analysis showed that the most downregulated pathways belonged to immune responses and complement activation while the most upregulated pathways were enriched predominantly in proliferation and development-related Gene Ontology biological processes. In total 2,753 differentially expressed genes (DEGs) coherent between these two populations were identified. To determinate, the subset of discriminant DEGs for colorectal adenomas, the output of seven feature selection methods was combined highlighting a total of 321 DEGs scored at the top 95% of at least one method. Further from this set, 8 candidate genes AXIN2, ETV4, RNF43, CXCL12, FBLN1, GNG7, ZEB2, and SFRP1 were selected for validation on a larger population as well as for functional in vitro assays. The results will be presented at the annual meeting. We believe that the study could provide new candidate biomarkers for precancerous colorectal cancer stages. Acknowledgement: This study was financed by NV18-03-00199. Citation Format: Anna Siskova, Veronika Vymetalkova, Pavel Vodicka, Giulio Ferrero, Alessio Naccarati, Chuanpit Hampel, Regine Schneider-Stock. Biomarkers of precancerous colorectal cancer stages identified by transcriptome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3368.